Abstract 4359390: Low-Dose Semaglutide Attenuates Coronary Artery Pathology and Improves Vascular Function Independent of Weight Loss in a Porcine Model of Cardiometabolic HFpEF

Background: Coronary microvascular dysfunction is a common finding in HFpEF and contributes to diastolic dysfunction, fibrosis, and exercise intolerance. Semaglutide, a GLP-1 receptor agonist (GLP-1RA) approved for obesity and diabetes, has demonstrated promising effects in cardiometabolic HFpEF clinical trials. Accumulating evidence suggests that GLP-1RAs exert direct cardiovascular benefits via activation of heart and vascular GLP-1 receptors. Hypothesis: Weight loss-independent benefits of semaglutide in HFpEF may involve the improvement of coronary vascular remodeling and function. Methods: Female Göttingen minipigs developed HFpEF through 8 weeks of DOCA treatment and a high-fat, Western diet containing 2% sodium. Subsequently, pigs (n=5 per group) were randomized to control or low-dose semaglutide (8 nmol/kg, IM, once weekly) for 12 weeks. We performed echocardiography, invasive systemic and LV hemodynamics, coronary histopathology and vascular function testing, fibrosis, and exercise testing. Results: Low-dose semaglutide failed to induce weight loss but improved LV diastolic function, and decreased LVEDP by 62% along with a similar reduction in PCWP. Control pigs exhibited substantial pericardial and epicardial adipose tissue accumulation, particularly surrounding the coronary arteries in conjunction with perivascular fibrosis. Semaglutide treatment significantly reduced pericardial and epicardial adipose tissue and attenuated perivascular fibrosis (p < 0.01). Furthermore, control pigs exhibited profound coronary artery medial thickening and increased media-to-lumen ratio, indicative of pathological coronary artery remodeling which were both significantly reduced by GLP-1 RA therapy. Semaglutide reversed coronary artery calcium deposition and fibrosis compared to control pigs. Consistent with the histological findings, ex vivo studies demonstrated that semaglutide enhanced coronary artery endothelium-dependent relaxation by 72% as compared to control vessels (p < 0.05). Summary and Conclusion: Low-dose GLP-1 RA therapy reverses coronary artery pathological remodeling in severe cardiometabolic HFpEF. These improvements in coronary vascular function likely result in improved myocardial function, exercise tolerance, and quality of life in HFpEF. Additional studies are required to confirm the direct vascular effects of GLP-1 RA therapy in HFpEF patients. Our data suggest a broader role of GLP-1R agonist therapy in the treatment of cardiovascular diseases.